Minor Glomerular Abnormalities are Associated with Deterioration of Long-Term Kidney Function and Mitochondrial Injury

Abstract

Minor glomerular abnormalities (MGAs) are unclassified glomerular lesions indicated by the presence of minor structural abnormalities that are insufficient for a specific pathological diagnosis. The long-term clinical outcomes and pathogenesis have not been examined. We hypothesized that MGAs would be associated with the deterioration of long-term kidney function and increased urinary mitochondrial DNA (mtDNA) copy numbers. We retrospectively enrolled patients with MGAs, age-/sex-/estimated glomerular filtration rate (eGFR)-matched patients with immunoglobulin A nephropathy (IgAN), and similarly matched healthy controls (MHCs; n = 49 each). We analyzed the time × group interaction effects of the eGFR and compared mean annual eGFR decline rates between the groups. We prospectively enrolled patients with MGAs, age-and sex-matched patients with IgAN, and MHCs (n = 15 each) and compared their urinary mtDNA copy numbers. Compared to the MHC group, the MGA and IgAN groups displayed differences in the time × group effects of eGFR, higher mean annual rates of eGFR decline, and higher urinary mtDNA copy numbers; however, these groups did not significantly differ from each other. The results indicate that MGAs are associated with deteriorating long-term kidney function, and mitochondrial injury, despite few additional pathological changes. We suggest that clinicians conduct close long-term follow-up of patients with MGAs.

Minimal Change Disease Is Associated with Mitochondrial Injury and STING Pathway Activation

“…To the best of our knowledge, this is the first study to investigate the role of mitochondrial injury in MCD pathogenesis and STING pathway activation in GN. Since urinary mtDNA levels are one of the most validated surrogate markers for mitochondrial injury in the kidney, and its clinical usefulness has been established in various kidney diseases [17,18,22,23,27], we used it to confirm that mitochondrial injury is involved in the MCD pathogenesis. Recently, we have conducted studies using urinary mtDNA for mitochondrial injury in GN pathogenesis.…”

“…The major limitation of several studies that investigated mitochondrial injury using urinary mtDNA in various kidney diseases was that the mitochondrial injury site could not be identified [17,18,22,23,27]. In these studies, the correlation with prognosis was analyzed under the premise that mitochondrial injury degree and urinary mtDNA levels would have a positive correlation, but there was no way to confirm this premise.…”

“…Considering that it is difficult to repeatedly perform a kidney biopsy, which is an invasive diagnostic method, additional experimental studies using animal models are necessary to confirm the change in mitochondrial injury degree during the natural course of MCD. Fourth, it is an important limitation that systemic mtDNA levels are not measured, as was the limitation of other GN studies using urinary mtDNA [23,27]. The possibility that urinary mtDNA increased as systemic mtDNA increased by other clinical factors was filtration into the urine cannot be excluded.…”

Roles of Mitochondrial DNA Damage in Kidney Diseases: A New Biomarker

“…In renovascular hypertensive patients, elevated urinary mtDNA copy numbers were correlated with mitochondrial dysfunction and renal injury, including increased urinary neutrophil gelatinase-associated lipocalin, kidney injury molecular-1 (KIM-1) levels and decreased estimated glomerular filtration [ 75 , 76 ]. Higher urinary mtDNA copy numbers and higher mean annual rates of estimated glomerular filtration rate (eGFR) decline were displayed in minor glomerular abnormalities and IgA nephropathy (IgAN) patients, and mitochondrial injury could be prior to pathological changes and increased proteinuria [ 77 , 78 ]. Urinary mtDNA was elevated in antineutrophil cytoplasmic autoantibodies-associated vasculitis (ANCA-AAV) patients suffering from abnormal kidney function and its level correlated with the severity of renal injury and pathological neutrophil infiltration [ 79 ].…”

Quantitative Analyses of Foot Processes, Mitochondria, and Basement Membranes by Structured Illumination

“…MGA is defined as an entity whose glomerular structure have minor changes using light microscopy, immunostaining, and electron microscopy albeit with urinary abnormality. 36 Scan parameters were optimized to obtain best signal/noise ratio (Table S5 and Figures S1-S4). The HE-stained sections excited at 457, 488, and 561 nm produced podocyte foot process images with a background signal from the glomerular basement membrane, while no obvious structures were visualized in the HE-stained sections excited at 640 nm (Figure 1a).…”